Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis
Yoichi Takimoto, Po–Sung Chu, Nobuhiro Nakamoto, Yuya Hagihara, Yohei Mikami, Kentaro Miyamoto, Rei Morikawa, Toshiaki Teratani, Nobuhito Taniki, Sota Fujimori, Takahiro Suzuki, Yuzo Koda, Rino Ishihara, Masataka Ichikawa, Akira Honda, Takanori Kanai∥
Abstract
The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b + cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4 -expressing Ly6c2 -low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro . Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo . These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.